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Systematic Review
Efficacy of Intra-articular Platelet-Rich
Plasma Injections in Knee Osteoarthritis:
A Systematic Review
Carlos J. Meheux, M.D., Patrick C. McCulloch, M.D., David M. Lintner, M.D.,
Kevin E. Varner, M.D., and Joshua D. Harris, M.D.
Purpose: To determine (1) whether platelet-rich plasma (PRP) injection significantly improves validated patient-reported
outcomes in patients with symptomatic knee osteoarthritis (OA) at 6 and 12 months postinjection, (2) differences in out-
comes between PRP and corticosteroid injections or viscosupplementation or placebo injections at 6 and 12 months post-
injection, and (3) similarities and differences in outcomes based on the PRP formulations used in the analyzed studies.
Methods: PubMed, Cochrane Central Register of Controlled Trials, SCOPUS, and Sport Discus were searched for English-
language, level I evidence, human in vivo studies on the treatment of symptomatic knee OA with intra-articular PRP
compared with other options, with a minimum of 6 months of follow-up. A quality assessment of all articles was performed
using the Modified Coleman Methodology Score (average, 83.3/100), and outcomes were analyzed using 2-proportion z-tests.
Results: Six articles (739 patients, 817 knees, 39% males, mean age of 59.9 years, with 38 weeks average follow-up) were
analyzed. All studies met minimal clinical important difference criteria and showed significant improvements in statistical and
clinical outcomes, including pain, physical function, and stiffness, with PRP. All but one study showed significant differences
in clinical outcomes between PRP and hyaluronic acid (HA) or PRP and placebo in pain and function. Average pretreatment
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were 52.36 and 52.05 for the PRP and HA
groups, respectively (P¼.420). Mean post-treatment WOMAC scores for PRP were significantly better than for HA at 3 to 6
months (28.5 and 43.4, respectively; P¼.0008) and at 6 to 12 months (22.8 and 38.1, respectively; P¼.0062). None of the
included studies used corticosteroids. Conclusions: In patients with symptomatic knee OA, PRP injection results in signifi-
cant clinical improvements up to 12 months postinjection. Clinical outcomes and WOMAC scores are significantly better after
PRP versus HA at 3 to 12 months postinjection. There is limited evidence for comparing leukocyte-rich versus leukocyte-poor
PRP or PRP versus steroids in this study. Level of Evidence: Level I, systematic review of Level I studies.
Osteoarthritis (OA) of the knee is a common
condition associated with pain and morbidity.
1
The increasing number of patients with symptomatic
OA will continue to place an increasingly large eco-
nomic burden on global health care systems.
1
Knee
arthroplasty is a reliable and successful surgical treat-
ment to address end-stage OA. Unfortunately, the cost
of and time delay to knee replacement is potentially
prohibitive in some countries. In the United States,
potential overutilization of arthroplasty is being met
with increasing scrutiny of preoperative nonsurgical
treatment.
2
This includes both nonpharmacological
and pharmacological approaches. Intra-articular corti-
costeroid and viscosupplementation injections have
successful, albeit short-term, benefits.
Recent American Academy of Orthopaedic Surgeons
clinical practice guidelines have demonstrated incon-
clusive evidence to recommend for or against cortico-
steroid and strong evidence against hyaluronic acid
(HA) viscosupplementation injections for patients with
symptomatic knee OA.
3
This has led to the emergence
From the Department of Orthopedics and Sports Medicine, Houston
Methodist Hospital, Houston, Texas, U.S.A.
The authors report the following potential conflicts of interest or sources of
funding: P.C.M. is on the Speaker’s Bureau/Paid Presentation of Genzyme;
receives research support from DePuy, a Johnson & Johnson Company,
Arthrex, and Zimmer; and is on the editorial/governing board of the Journal
of Knee Surgery and Orthobullets.com. K.E.V. receives IP royalties from
Solana and is a paid consultant for Solana, Stock, and Wright Medical.
J.D.H. is on the editorial board of Arthroscopy, the Journal of Arthro-
scopic and Related Surgery, and Frontiers in Surgery and receives
publication royalties from SLACK.
Received June 7, 2015; accepted August 6, 2015.
Address correspondence to Joshua D. Harris, M.D., Houston Methodist
Orthopedics and Sports Medicine, 6550 Fannin Street, Smith Tower, Suite
2500, Houston, Texas 77030, U.S.A. E-mail: joshuaharrismd@gmail.com
Ó2015 by the Arthroscopy Association of North America
0749-8063/15518/$36.00
http://dx.doi.org/10.1016/j.arthro.2015.08.005
Arthroscopy: The Journal of Arthroscopic and Related Surgery, Vol -,No-(Month), 2015: pp 1-11 1
of other injectable options for symptom relief and
functional improvement in these patients.
Platelet-rich plasma (PRP) is an autologous derivative
of whole blood that contains high concentrations of
growth factors including transforming growth factor-
b
,
insulin-like growth factor, platelet-derived growth fac-
tor, basic fibroblast growth factor, and vascular endo-
thelial growth factor, as well as bioactive proteins that
influence the healing of tendon, ligament, muscle, and
bone.
4
As a result, it has been studied for its efficacy in
management of various pathologies including but not
limited to OA, lateral epicondylitis, rotator cuff disease,
Achilles and patella tendinopathy, hamstring injuries,
and degenerative spine disease.
5-10
Through the effects
of the various growth factors, PRP has been shown to
have a positive effect on chondrogenesis and mesen-
chymal stem cell proliferation.
4
PRP has also been
shown to increase anti-inflammatory and decrease
proinflammatory mediators (Table 1). Evidence has
shown a reduction in the transactivation of nuclear
factor-kappa B, the critical regulator of the inflamma-
tory process.
4
PRP also decreases the expression of
inflammatory enzymes cycloxygenase 2 and 4, metal-
loproteinases, and disintegrins.
11,12
These combined
effects of PRP make it a potential injectable option for
management of OA.
Clinically, the comparative efficacy and effectiveness
of intra-articular injections of PRP, HA, and corticoste-
roid in the treatment of knee OA are unclear and
controversial. There are limited studies comparing these
options, and there are variations in the treatment
approach including subject-, knee-, and outcome-
specific variables including PRP preparation tech-
niques, platelet count, severity of OA, number of
injections, and molecular weight of HA.
13-15
There have
been numerous studies investigating the effects of PRP
or HA in the treatment of knee OA, but most do not
compare these 2 or use a control group.
13,16
The purpose of this systematic review was (1) to
determine whether PRP injection is able to significantly
improve validated patient-reported outcomes in
patients with OA of the knee at 6 and 12 months
postinjection, (2) to determine whether there is a sig-
nificant difference in outcomes between PRP and vis-
cosupplementation or PRP and placebo injections at
6 and 12 months postinjection; and (3) to determine
the similarities and differences between the variety of
PRP formulations used in the analyzed studies. It was
hypothesized that (1) PRP injections will significantly
improve validated patient-reported outcomes in pa-
tients with OA of the knee at 6 to 12 months post-
injection, (2) there will be a significant difference in
outcomes between PRP and viscosupplementation or
PRP and placebo at 6 and 12 months postinjection, and
(3) different preparations of PRP will yield significantly
different results.
Methods
A systematic review was registered on PROSPERO on
August 12, 2014 (registration ID: CRD42014013032).
Preferred Reporting Items for Systematic Reviews and
Meta-Analyses guidelines were followed.
17
English-
language original research therapeutic level I evidence
(based on Oxford Centre for Evidence Based Medicine)
randomized comparative trials were eligible for inclu-
sion.
18
The studies that were sought compared the use of
autologous PRP with HA viscosupplementation, cortico-
steroid, placebo, or other intra-articular injections for the
treatment of symptomatic knee OA in humans with a
minimum follow-up of 6 months. Basic science ex vivo
and in vitro studies, levels II, III, IV, or V evidence, letters
to the editor, nonknee OA, asymptomatic OA, and PRP
compared with surgical options were excluded.
Separate electronic searches of the following data-
bases were conducted: PubMed, Cochrane Central
Register of Controlled Trials, SCOPUS, and Sport
Discus. The searches were performed on February 12,
2015. The search terms used including “platelet-rich
plasma knee osteoarthritis”,“platelet rich plasma
gonarthrosis”, and “platelet rich plasma knee degener-
ative joint disease”were entered as medical subject
headings for searches in all the databases used. The
search results were reviewed for duplicates and the
inclusion criteria to determine articles that were
included in the final analysis (Fig 1).
Two authors (C.J.M. and J.D.H.) independently
reviewed all articles using the methodology recom-
mended by Harris et al.
19
The study type and design,
methods, level of evidence, and populations enrolled
were first identified. Primary and secondary outcomes
were analyzed. This information was used to reach a
consensus based on the conclusions made by the au-
thors of the original studies.
Because of the heterogeneity of outcome measures,
a best-evidence synthesis
20
was used instead of a
meta-analysis. The results of the quality assessments of
the individual studies were used to classify the level of
evidence.
21
This qualitative analysis was performed
Table 1. Effects of Platelet-Rich Plasma on Inflammation and
Metabolism
Increases
Anti-inflammatory
Markers
Decreases
Proinflammatory
Markers Anabolic Effects
Aggregan Cyclooxygenases Proteoglycan
synthesis
Metalloproteinases Cartilage
regeneration
Disintegrins
Tumor necrosis factor alpha
Interferon gamma
Selectins
Interleukin-1
2C. J. MEHEUX ET AL.
with 5 levels of evidence based on the quality and
results of the included studies.
22
In addition, study
methodological quality was analyzed using the Modi-
fied Coleman Methodology Score (MCMS).
23
Descrip-
tive statistics were calculated using the mean
standard deviation for quantitative continuous data and
frequencies with percentages for qualitative categorical
data. Comparisons in outcome scores at pre- and post-
injection time points and between PRP and HA groups
were made using the 2-proportion z-test calculator
(http://in-silico.net/tools/statistics/ztest) using alpha
0.05 because of the difference in sample sizes between
compared groups.
Results
Six articles (739 patients, 817 knees) were analyzed
(Table 2). There were 39% males and 61% females
with a mean age of 59.9 years per patient and 59.2
years per knee and mean follow-up of 38 weeks per
patient and 37 weeks per knee. Radiographically, the
Kellgren-Lawrence and Ahlback grading systems were
used determine severity of knee OA. Two studies used
the Ahlback classification system and showed that
58.2% were grade I, 32.4% were grade II, and 9.4%
were grade III. Four studies used the Kellgren-
Lawrence classification and showed that 8.7% were
grade I, 40.7% were grade II, 37.9% were grade III, and
12.6% were grade IV. The Filardo et al. study only re-
ported average Kellgren-Lawrence grades for HA and
PRP groups (2.1 and 2.2, respectively) and therefore
was not included in the grade-percentage stratification
above. According to the MCMS, 3 articles were excel-
lent (with scores of 85 or greater), and 3 were good
(scores between 70 and 84), with a mean score of 83.3/
100. The Western Ontario and McMaster Universities
Osteoarthritis Index (WOMAC) was the most
frequently used outcome score (5 of 6 studies), how-
ever, one of 6 used International Knee Documentation
Committee (IKDC), one of 6 used Knee Injury and
Osteoarthritis Outcome Score (KOOS), one of 6 used
Short Form-36, one of 8 used Tegner, 2 of 6 used the
visual analog scale (VAS), and 2 of 6 used Lequesne.
PRP significantly improved validated patient-reported
outcomes, according to WOMAC and IKDC scores, in
patients with OA of the knee at 6 and 12 months post-
injection (Table 3). PRP was also shown to be better than
HA at improving patient outcomes. The outcomes eval-
uated included pain, physical function, and stiffness.
According to 2-proportion z-tests, the average pretreat-
ment WOMAC scores for PRP and HA were 52.36 and
52.05, respectively (P¼.420), among studies that
compared both treatment modalities. At 12 to 26 weeks,
the average WOMAC scores for PRP and HA treatments
were 28.5 and 43.4, respectively, with a significant
Fig 1. Flow diagram sum-
marizing the literature
search, screening, and
review.
PRP INJECTIONS IN KNEE OSTEOARTHRITIS 3
Table 2. Demographics and Methods of the Various Clinical Trials
Publication year Cerza et al.
27
2012 Filardo et al.
28
2012 Patel et al.
29
2013 Sanchez et al.
30
2012 Vaquerizo et al.
31
2013 Raeissadat et al.
32
2014
Subject enrollment date September
2009-September
2010
Not recorded Not recorded January
2008-November
2009
Not recorded Not recorded
Country, Continent Italy, Europe Italy, Europe India, Asia Spain, Europe Spain, Europe Iran, Asia
Conflict of interest None None Not mentioned None Not mentioned None
No. of subject (knees) 120 (120) 109 (109) 78 (156) 176 (176) 96 (96) 160 (160)
Gender: male, female 53, 67 68, 41 22, 53 85, 91 38, 58 23, 116
Mean age 66.4 56.5 52.8 59.8 63.6 58.8
Bilateral vunilateral
knee injections
Unilateral Unilateral Bilateral Unilateral Unilateral Unilateral
Right vleft 91 right, 29 left Not recorded 78 left, 78 right Not recorded Not recorded Not recorded
Study Group 1 60 patients
received 4 weekly
intra-articular
injections of PRP
54 patients
received 3 weekly
intra-articular
injections of PRP
26 patients (52 knees)
received a single injection
of PRP and 25 patients
(50 knees) received 2
injections of PRP 3
weeks apart
87 patients
received
3 weekly
intra-articular
PRGF-Endoret
48 patients
received
3 biweekly
intra-articular
PRGF-Endoret
87 patients
received 2
intra-articular
injections of PRP
4 weeks apart
Study Group 2 60 patients
received 4 weekly
intra-articular
injections of HA
55 patients
received 3 weekly
intra-articular
injections of HA
23 patients (46 knees)
received a single injection
of normal saline (8 mL)
89 patients
received
3 weekly
intra-articular HA
48 patients who
received 1
intra-articular HA
73 patients
received
3 weekly
intra-articular HA
Radiographic
classification
Kellgren-Lawrence
Grade I: 25
Grade II: 22
Grade III: 13
Kellgren-Lawrence
Average of Grade
2.2 for PRP group
and Grade 2.1 for
HA group
Ahlback
Grade I: 98
Grade II: 39
Grade III: 7
Ahlback
Grade I: 87
Grade II: 64
Grade III: 23
Kellgren-Lawrence
Grade II: 32
Grade III: 47
Grade IV: 17
Kellgren-Lawrence
Grade I: 6
Grade II: 91
Grade III: 75
Grade IV: 28
Length of
follow up
24 weeks 12 months 6 months 24 weeks 48 weeks 52 weeks
Outcome
scores used
WOMAC IKDC, TEGNER,
KOOS, EQ-VAS
WOMAC, VAS WOMAC, Lequesne WOMAC, Lequesne,
OMERACT-OARSI
WOMAC, SF-36
Prior surgeries No 63 subjects No Not recorded Not recorded Not recorded
Prior Injections No Not recorded none in prior 3 months none in prior
3 months
none in prior 6 months None in prior 2 weeks
Prior physical
therapy
Yes Not recorded Not recorded Not recorded Not recorded Not recorded
Post injection
treatments
None None None None None Physical therapy
Use of NSAIDs (few
days pre injection
and immediate
post-injection)
No No Not recorded No None None
Use of cryotherapy
post-injection
No Yes No No Not recorded No
Injection approach Superolateral Not recorded Superolateral Not recorded Superolateral Anteromedial or
Lateral midpatellar
(continued)
4C. J. MEHEUX ET AL.
difference (P¼.0008) favoring PRP over HA. At 26 to 52
weeks, the average WOMAC scores for PRP and HA
treatments were 22.8 and 38.1, respectively, with a sig-
nificant difference (P¼.0062) favoring PRP over HA.
Therewasasignificant difference between pre-PRP and 4
to6weeks(P¼.047),6to12weeks(P¼.006),12to26
weeks (P<.001), and 26 to 52 weeks (P<.001). There
was no significant difference between 4 to 6 weeks and 6
to 12 weeks (P¼.52); 6 to 12 weeks and 12 to 26 weeks
(P¼.26); and 12 to 26 weeks and 26 to 52 weeks
(P¼.21). WOMAC was most frequently used outcome
score (5/6 studies). All post-PRP time points up to 12
months were significantly better than preinjection in
WOMAC score. The distribution-based method using the
standard error of measurement was used to determine
the minimal clinical important difference (MCID). A
difference in WOMAC and IKDC scores of at least one
standard error of measurement was considered the cri-
terion for achieving MCID.
24
The WOMAC and IKDC
scores analyzed in this review revealed true MCID in
outcomes.
All studies showed significant clinical and statistical
improvements in outcomes at 3 to 12 months of follow-
up, including pain, physical function, and stiffness, with
the use of PRP in treating knee OA according to
WOMAC and IKDC scores. All but one study showed
significant differences between PRP and HA or PRP and
placebo in clinical outcomes of improvement of pain
and function for at least 6 to 12 months. One study
compared PRP to saline (placebo), and no studies
compared PRP to corticosteroid injection.
No study compared leukocyte-poor PRP to leukocyte-
rich PRP. However, all studies except Filardo et al. used
leukocyte-poor PRP, and all studies except Filardo et al.
showed significant clinical and statistical improvements
on WOMAC scores between HA and PRP or HA and
placebo groups. The studies used different PRP prepara-
tions with 3 of 6 using calcium chloride activator, one of
6 used leukocyte-rich PRP, 4 of 6 using the single spin
approach, and 2 of 6 using the double spin approach
(Table 4). The different PRP systems used were also
classified using the PAW classification system, a classifi-
cation system for PRP that looks at platelet concentration,
activation method, and white blood cell (WBC) count.
25
Owing to the fact that the only outcomes that were
able to be compared were those of WOMAC scores as
indicated above, the best-evidence synthesis is moder-
ate and the summary of recommendation taxonomy is
“B”for this review.
22,26
Discussion
It was determined that intra-articular PRP injections
significantly improve the clinical outcomes in symp-
tomatic knee OA. PRP was also shown to be signifi-
cantly better than HA or placebo for the treatment of
symptomatic knee OA. Treating OA nonoperatively has
Table 2. Continued
Publication year Cerza et al.
27
2012 Filardo et al.
28
2012 Patel et al.
29
2013 Sanchez et al.
30
2012 Vaquerizo et al.
31
2013 Raeissadat et al.
32
2014
Control group
injection
HA 20 mg/2 mL;
Hyalgan; Fidia,
Abano Terme,
Italy
HA >150 Kda,
Hyalubrix; Fidia,
Abano Terme,
Italy
Normal saline HA, Euflexxa;
Copenhagen,
Denmark
Durolane (Non-animal
stabilized HA); Q-MED
AB, Uppsala, Sweden
Hyalgan (High molecular
weight HA; 500
Kda - 730 Kda);
Fifia Farmaceutici
S.p.A, Abano Terme,
Italy
Primary and
secondary
outcomes
WOMAC score
before the
infiltration and
at 4, 12, and 24
weeks after the
first injection
IKDC, EQ-VAS,
TEGNER, and KOOS
scores, range of
motion and knee
circumference
changes were
evaluated at 2,
6 and 12 months
WOMAC at 6 weeks,
3 months, and 6
months
WOMAC scores
at 1, 2, and
6 months
WOMAC and Lequesne
scores at 24 and
48 weeks
WOMAC and SF-36
scores at 52 weeks
NOTE. Patel et al.
29
had 78 patients with bilateral knee osteoarthritis, all of which were included in the study, and this study had 3 separate treatment groups (2 with PRP, one with HA). The
level of evidence for all trials was level I. Knee range of motion was not recorded for any trial.
EQ-VAS, EuroQol visual analog scale; IKDC, International Knee Documentation Committee; KOOS, Knee Injury and Osteoarthritis Outcome Score; PRGF-Endoret, platelet-rich growth
factor-Endoret; PRP, platelet-rich plasma; SF-36, Short Form-36; TEGNER, Tegner activity score; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.
PRP INJECTIONS IN KNEE OSTEOARTHRITIS 5
Table 3. Summary of Results Including WOMAC, VAS, Tegner, Lequesne, IKDC, and SF-36 Scores from the Various Studies
Articles Pretreatment
Early
(4-6 Weeks)
Mid
(6-12 Weeks) Late (12-26 Weeks)
Extended
(26-52 Weeks)
Cerza et al.
27
ACP: WOMAC
76.9 9.5
HA: WOMAC
75.4 10.7
ACP: WOMAC
49.6 17.7
HA: WOMAC
55.2 12.3
(P<.001) between
groups
ACP: WOMAC
39.1 17.8
HA: WOMAC
57 11.7
(P<.001) between
groups
ACP: WOMAC
36.5 17.9
HA: WOMAC
65.1 10.6
(P<.001) between
groups
DNC
Filardo et al.
28
PRP: IKDC score
50.2 15.7
Tegner score
2.9 1.4
HA: IKDC score
47.4 15.7
Tegner score
2.6 1.2
DNC PRP: IKDC score
62.8 17.6
HA: IKDC score
61.4 16.2
PRP: IKDC score
64.3 16.4
HA: IKDC score
61.0 18.2
PRP: IKDC score 64.9 16.8
Tegner score 3.8 1.3
HA: IKDC score 61.7 19.0
Tegner score 3.4 1.6
Pvalues not recorded
Patel et al.
29
PRP1: WOMAC
49.86 17.83
VAS 4.56 0.61
PRP2: WOMAC
53.20 16.18
VAS 4.64 0.56
Saline: WOMAC
45.54 17.29
VAS 4.57 0.62
PRP1: WOMAC 25.36
PRP2: WOMAC 24.96
Saline: WOMAC 46.78
PRP1: WOMAC 22.48
PRP2: WOMAC 25.70
Saline: WOMAC 50.70
PRP1: WOMAC 27.18
VAS 2.16 1.543
PRP2: WOMAC 30.48
VAS 2.54 1.717
Saline: WOMAC 53.09
VAS 4.61 0.745
WOMAC: percentage benefit
from baseline at each follow
up was greater in PRP1 and
PRP2 than Saline (P<.001)
with no difference between
PRP1 and PRP2.
VAS pain reduction benefit for
the PRP1 and PRP 2 groups
(P¼.001) with no significant
benefit between the groups
(P¼.410). No VAS pain
reduction benefit for saline
group (P¼.598)
DNC
Sanchez et al.
30
PRGF: WOMAC
121.8 44.4
Lequesne 9.5 3.0
HA: WOMAC
115.6 45.1
Lequesne 9.1 3.2
DNR DNR PRGF: WOMAC 74.0 42.7
38.2% of patients had 50%
decrease in WOMAC pain
score 57.3% of patients had
20% decrease in WOMAC
pain scoreLequesne 5.2 3.4
HA: WOMAC 78.3 48.1
24.1% of patients had 50%
decrease in WOMAC pain
DNC
(continued)
6C. J. MEHEUX ET AL.
Table 3. Continued
Articles Pretreatment
Early
(4-6 Weeks)
Mid
(6-12 Weeks) Late (12-26 Weeks)
Extended
(26-52 Weeks)
score. 52.9% of patients had
20% decrease in WOMAC
pain score. Lequesne 5.4 3.3
Differences between PRGF and
HA for 50% decrease
in WOMAC pain score
(P¼.044), for 20% decrease
(P¼.555), for total WOMAC
score (P¼.561), and for Lequesne
score (P¼.714)
Vaquerizo et al.
31
PRGF: WOMAC
45.9 12.7
Lequesne
12.8 3.8
HA: WOMAC
50.8 18.4
Lequesne 13.1 38
DNC DNC For patients with 30% decrease in:
WOMAC summed score: rate of
response of PRGF was 66, 43, and
23 percentage points higher than
that of HA for pain, physical function
and stiffness, respectively (P<.001,
P<.001, P¼.02, respectively).
Lequesne score: PRGF group is 56
percentage points higher than HA
group (P<.001)
For patients with 50% decrease in:
WOMAC summed score: rate of
response of PRGF was 43, 29, and
19 percentage points higher than
that of HA for pain, physical function
and stiffness, respectively (P<.001,
P¼.001, P¼.035, respectively).
Lequesne score: PRGF group is 25
percentage points higher than HA
group (P¼.002)
For patients with 30% decrease in:
WOMAC summed score: rate of
response of PRGF was 46, 37,
and 40 percentage points higher
than that of HA for pain, physical
function and stiffness, respectively
(P<.001, P<.001, P<.001,
respectively). Lequesne score:
PRGF group 46 percentage points
higher than HA group (P<.001)
For patients with 50% decrease in:
WOMAC summed score: rate of
response of PRGF was 29-, 31-,
and 28 percentage points higher
than that of HA for pain, physical
function and stiffness, respectively
(P<.001, P<.001, P¼.001,
respectively). Lequesne score: 19
and 2 percentage points in the
PRGF and HA groups, respectively
Raeissadat et al.
32
PRP: WOMAC
39.5 17.06
SF-36 (PCS)
178.14 81.0
SF-36 (MCS)
229.22 95.62
HA: WOMAC
28.69 16.69
SF-36 (PCS)
180.4 68.52
SF-36 (MCS)
226.43 97.39
DNC DNC DNC PRP: WOMAC
18.44 14.35
(P<.001)SF-36
(PCS) 255.96 77.59
(P<.001)SF-36 (MCS)
269.92 91.48 (P<.001)
HA: WOMAC 27.46 16.36
(P¼.009)SF-36 (PCS)
189.39 103.73 (P¼.37)
SF-36 (MCS) 216.91 100.9
(P¼.74)
(continued)
PRP INJECTIONS IN KNEE OSTEOARTHRITIS 7
been ongoing for several decades. Multiple studies have
reported the use of HA, PRP, and corticosteroids, among
other agents, in the nonoperative treatment of OA.
While there are a good amount of studies documenting
the use of HA in the treatment of knee OA, there are
limited studies documenting the use of PRP for the
same purpose. More importantly, there are very limited
studies comparing the use of PRP with that of HA or
PRP with placebo in the treatment of knee OA.
27-32
This
study’s aim was to determine whether PRP injection is
able to significantly improve validated patient-reported
outcomes in patients with OA of the knee, determine
whether there is a significant difference in outcomes
between PRP and viscosupplementation or PRP and
placebo injections, and evaluate the similarities and
differences between the variety of PRP formulations
used in the analyzed studies. The hypotheses that (1)
PRP injections will significantly improve validated
patient-reported outcomes in patients with OA of the
knee and (2) that there will be significant differences in
outcomes between PRP and viscosupplementation or
PRP and placebo were confirmed; the third hypothesis
that different preparations of PRP will yield significantly
different results was inconclusive. Clinicians should use
PRP in patients with symptomatic knee OA with Ahl-
back grades I to III or Kellgren-Lawrence grades I to III.
PRP injections can be administered in 2 to 4 sessions, 2
to 4 weeks apart. This recommendation is based on
ranges used in the studies included in this review.
Multiple studies have shown improved patient out-
comes with the use of PRP for the treatment of knee
OA. Gobbi et al. tried to determine the effectiveness of
intra-articular PRP injections in active patients with
knee OA and to evaluate clinical outcomes in patients
with and without previous surgical treatment for
cartilage lesions.
33
The PRP treatment showed positive
effects in patients with knee OA. Operated and non-
operated patients showed significant improvement by
means of pain reduction and improved symptoms and
quality of life.
Autologous PRP injections have shown more and
longer efficacy than HA injections in reducing pain and
function and recovering articular function.
15
Three
homogenous groups of patients were treated with
3 injections of PRP, low molecular weight HA, and high
molecular weight HA. The results showed better per-
formance for PRP group at 6 months of follow-up. This
study also showed that younger and more active
patients achieved better results with a low degree of
cartilage degeneration.
There are many PRP systems, some of which have
higher concentrations of WBCs, with others having
higher concentrations of growth factors but not the
additional concentration of WBCs. Since neutrophils
are the most abundant type of WBCs, excessive
neutrophil infiltration has been associated with chronic
Table 3. Continued
Articles Pretreatment
Early
(4-6 Weeks)
Mid
(6-12 Weeks) Late (12-26 Weeks)
Extended
(26-52 Weeks)
Average WOMAC
scores across studies
PRP: 52.36
HA: 52.05
No significant difference
(P¼.420) between PRP
and HA groups
PRP: 28.5
HA: 43.4
Significant difference
(P¼.0008) favoring
PRP over HA
PRP: 22.8
HA: 38.1
Significant difference
(P¼.0062) favoring PRP over HA
NOTE. To assess the severity of gonarthrosis, the sum of all points is determined, with a minimum score of 0 and a maximum of 24, where 0 indicates no severity; 1-4, mild; 5-7, moderate; 8-
10, severe; 11-13, very severe; and 14 or greater, extremely severe. Average WOMAC scores for the studies that compared PRP versus HA with follow-up of at least 12-26 weeks with P-values
determined by 2-proportion z-tests were included.
ACP, autologous conditioned plasma; DNC, study did not collect data during this time period; DNR, study collected data but did not report the numbers on the manuscript; IKDC, Inter-
national Knee Documentation Committee; MCS, mental component of SF-36; PCS, physician component of SF-36; PRGF-Endoret (platelet-rich growth factor-Endoret); SF-36, Persian form of
short form 36; TEGNER, Tegner activity score; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index; Lequesne score is an index of severity for osteoarthritis of the knee
that includes 3 subscales (pain or discomfort, maximum distance walked, and activities of daily living).
8C. J. MEHEUX ET AL.
inflammation and delayed wound healing. Through
phagocytosis, macrophages are known to clear up the
particulate debris that accumulates after neutrophil
activation and release of proteolytic enzymes.
34
Several
studies have investigated the effects of leukocyte-poor
versus leukocyte-rich PRP in tissue healing. PRP rich
in leukocytes have been shown to cause a significantly
greater acute inflammatory response and increased
synoviocyte cell death.
35,36
Despite having similar
safety profiles, leukocyte-rich PRP and leukocyte-poor
PRP were shown to both induce more transient
reactions than does HA.
37
Of the studies included in this
review, the Filardo et al. study used leukocyte-rich PRP,
which showed improved outcomes in the parameters
measured but no significant differences when
compared to HA. All other studies included in this
review used leukocyte-poor PRP and all showed
improved outcomes in the parameters measured as well
as significant differences when compared to HA or
placebo. Given that none of the studies included in this
review directly compared leukocyte-rich PRP versus
leukocyte-poor PRP, a conclusion comparing the effects
of these formulations on treatment of symptomatic
knee OA cannot be made, and it will be an area of focus
for future research.
Limitations
There were some limitations and biases noted
among the studies includedinthisreview.Withthe
exception of Sanchez et al.,
30
none of the reviews
used a double-blinded approach. Even though Patel
et al.
29
reported that their study was double-blinded,
it is noted that 2 out of the 3 study groups received
one injection while the other received 2 injections.
This variation in intervention makes it difficult to
blind the participants, and it remains unclear whether
performance bias is present. Also, Cerza et al.
27
and
Patel et al.
29
did not report their randomization pro-
cedures. The results reported by these studies could be
affected by the randomization and blinding appro-
aches. The studies included reported follow-ups of up
to 12 months in 3 papers and 6 months in 3 papers.
Longer-term follow-ups will provide a better sense of
the long-term effects of the interventions. Radio-
graphic data were not collected at follow-up visits in
any of the studies, and this information would have
been useful in providing additional objective data for
analysis. Given data from the MCMS, future studies
can improve on looking at longer-term follow-ups of
at least 2 years, including postinjection rehabilitation
protocols, and providing adequate and consistent
description of injection techniques used.
All but one study used WOMAC scores, with the
outlier using IKDC scores together with KOOS and
Tegner. WOMAC and IKDC both meet MCID and MDC
criteria and have better test-retest reliability and
Table 4. Platelet-Rich Plasma (PRP) Preparation and Characteristics and Use of Ultrasound Guidance for Verification of Injection in Knee Joint
Article
PRP Spinning
Approach
Duration of
Spin (Minutes) Company
PRP
Activator
PRP Volume Injected
(mL)/No. of Injections
Platelet
Concentration
White Blood
Cell Count
PAW
Classification
Cerza et al.
27
Single NR Biocore, Arthrex Inc,
Karlsfeld, Germany
None 5.5/4 >5baseline Low P4-B
Filardo et al.
28
Double 6 and 15aNR NR 8/3 5baseline 1.2baseline P4-A
Patel et al.
29
Single 15 PGIMER CaCl
2
8/1 and 2b<5baseline 0 P2-B/P3-B
Sanchez et al.
30
Single 8 BTI, Biotechnology
Institute, Vitoria, Spain
CaCl
2
8/3 <5baseline Low P2-B/P3-B
Vaquerizo et al.
33
Single 8 BTI, Biotechnology
Institute, Vitoria, Spain
CaCl
2
8/3 <5baseline Low P2-B/P3-B
Raeissadat et al.
32
Double 15 and 7aArya Mabna Tashkis Corp. None 4-6/2 5.2and 4.8
baselinec780 and 808 cells/
m
L P4-B
NOTE. No ultrasound guidance was used in any study.
NR, not recorded; PAW classification, classification system for PRP that looks at platelet concentration, activation method, and white blood cell count
25
; PGIMER, Department of transfusion
Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
a
Represents times for first and second centrifugation.
b
One group received one injection, and the other group received 2 injections.
c
Averages for first and second injections, respectively.
PRP INJECTIONS IN KNEE OSTEOARTHRITIS 9
internal consistency compared with KOOS and
Tegner.
24
Thus WOMAC and IKDC are the best
outcome scores for knee OA studies. Future studies can
improve with using both WOMAC and IKDC tools
simultaneously.
There are several limitations of this review. The number
of studies (n ¼6) included in this review is small. Also,
one of the 6 studies included compared PRP to placebo,
while the others compared PRP to HA. Another possible
limitation of this review is that other relevant studies on
this topic could have been excluded, despite conducting a
systematic search. Given that we found many duplicate
studies among several databases, we do not feel that
many studies, if any at all, were omitted.
Conclusions
In patients with symptomatic knee OA, PRP injection
results in significant clinical improvements up to 12
months postinjection. Clinical outcomes and WOMAC
scores are significantly better after leukocyte-poor PRP
versus HA at 3 to 12 months postinjection. There is
limited evidence for comparing leukocyte-rich versus
leukocyte-poor PRP in this study.
References
1. Curl WW, Krome J, Gordon ES, Rushing J, Smith BP,
Poehling GG. Cartilage injuries: a review of 31516 knee
arthroscopies. Arthroscopy 1997;13:456-460.
2. Riddle DL, Jiranek WA, Hayes CW. Use of a validated al-
gorithm to judge the appropriateness of total knee arthro-
plasty in the United States: a multicenter longitudinal
cohort study. Arthritis Rheumatol 2014;66:2134-2143.
3. Brown GA. AAOS clinical practice guidelines. Treatment
of osteoarthritis of the knee: evidence-based guideline, 2d
ed. J Am Acad Orthop Surg 2013;21:577-579.
4. Kabiri A, Esfandiari E, Esmaeili A, Hashemibeni B,
Pourazar A, Mardani M. Platelet-rich plasma application
in chondrogenesis. Adv Biomed Res 2014;3:138.
5. Sundman EA, Cole BJ, Karas V, et al. The anti-
inflammatory and matrix restorative mechanisms of
platelet-rich plasma in osteoarthritis. Am J Sports Med
2014;42:35-40.
6. Sadoghi P, Rosso C, Valderrabano V, Leithner A,
Vavken P. The role of platelets in the treatment of Achilles
tendon injuries. J Orthop Res 2013;31:111-118.
7. Malavolta EA, Gracitelli ME, Ferreira Neto AA,
Assunção JH, Bordalo-Rodrigues M, de Camargo OP.
Platelet-rich plasma in rotator cuff repair: a prospective
randomized study. Am J Sports Med 2014;42:2446-2454.
8. Dragoo JL, Wasterlain AS, Braun HJ, Nead KT. Platelet-
rich plasma as a treatment for patellar tendinopathy. A
double-blind, randomized controlled trial. Am J Sports Med
2014;42:610-618.
9. A Hamid MS, Mohamed Ali MR, Yusof A, George J,
Lee LP. Platelet-rich plasma injections for the treatment
of hamstring injuries: a randomized controlled trial.
Am J Sports Med 2014;42:2410-2418.
10. Kim HJ1, Yeom JS, Koh YG, et al. Anti-inflammatory
effect of platelet-rich plasma on nucleus pulposus cells
with response of TNF-
a
and IL-1. J Orthop Res 2014;32:
551-556.
11. van Buul GM, Koevoet WL, Kops N, et al. Platelet-rich
plasma releasate inhibits inflammatory processes in oste-
oarthritic chondrocytes. Am J Sports Med 2011;39:
2362-2370.
12. Bendinelli P, Matteucci E, Dogliotti G, et al. Molecular
basis of anti-inflammatory action of platelet-rich plasma
on human chondrocytes: mechanisms of NF-kappa B in-
hibition via HGF. J Cell Physiol 2010;225:757-766.
13. Nguyen RT, Borg-Stein J, McInnis K. Applications of
platelet-rich plasma in musculoskeletal and sports
medicine: an evidence-based approach. PM&R 2011;3:
226-250.
14. Sheth U, Simunovic N, Klein G, et al. Efficacy of autol-
ogous platelet-rich plasma use for orthopaedic in-
dications: a meta-analysis. J Bone Joint Surg Am 2012;94:
298-307.
15. Kon E, Mandelbaum B, Buda R, et al. Platelet intra-articular
injection versus hyaluronic acid viscosupplementation as
treatments for cartilage pathology: from early degenerations
to osteoarthritis. Arthroscopy 2011;27:1490-1501.
16. Strauss EJ, Hart JA, Miller MD, Altman RE, Rosen JE.
Hyaluronic acid viscosupplementation and osteoarthritis:
current uses and future directions. Am J Sports Med
2009;37:1636-1644.
17. Moher D, Liberati A, Tetzlaff J, Altman DG, the PRISMA
Group. Preferred reporting items for systematic reviews
and meta-analyses: the PRISMA Statement. PLoS Med
2009;6(7):e1000097.
18. Howick J, Chalmers I, Glasziou P, et al. The 2011 Oxford
CEBM Evidence Levels of Evidence (Introductory Docu-
ment). Oxford Centre for Evidence-Based Medicine.
Available at: http://www.cebm.net/index.aspx?o¼5653.
Accessed June 1, 2015.
19. HarrisJD,QuatmanCE,ManringMM,SistonRA,
Flanigan DC. How to write a systematic review. Am J Sports
Med 2014;42:2761-2768.
20. Slavin RE. Best evidence synthesis: an intelligent alter-
native to metaanalysis. J Clin Epidemiol 1995;48:9-18.
21. Editorial Board of the Cochrane Collaboration Back Re-
view Group. Updated method guidelines for systematic
reviews in the cochrane collaboration back review group.
In: van Tulder M, Furlan A, Bombardier C, Bouter L, eds.
Spine 2003;28:1290-1299.
22. Owens DK, Lohr KN, Atkins D, et al. Grading the strength
of a body of evidence when comparing medical in-
terventions. In: Agency for Healthcare Research and
Quality. Methods Guide for Comparative Effectiveness
Reviews (posted July 2009). Rockville, MD. Available at:
http://effectivehealthcare.ahrq.gov/healthInfo.cfm?info
type¼rr&ProcessID¼60. Accessed June 1, 2015.
23. Cowan J, Lozano-Calderon S, Ring D. Quality of pro-
spective controlled randomized trials. analysis of trials of
treatment for lateral epicondylitis as an example. J Bone
Joint Surg Am 2007;89:1693-1699.
24. AOSSM Outcomes Task Force, Irrgang J. Summary of
clinical outcomes measure for sports-related knee injuries.
Available at: http://www.sportsmed.org/uploadedFiles/
10 C. J. MEHEUX ET AL.
Content2/Research/Research_Resources/SummaryReport_
June%2029%202012.pdf. Accessed March 1, 2015.
25. DeLong JM, Russell RP, Mazzocca AD. Platelet-rich
plasma: the PAW classification system. J Arthroscopy
Related Surg 2012;28:998-1009.
26. Ebell MH, Siwek J, Weiss BD, et al. Strength of recom-
mendation taxonomy (SORT): a patient-centered
approach to grading evidence in the medical literature.
Am Fam Physician 2004;69:549-557.
27. Cerza F, Carni S, Carcangiu A, et al. Comparison between
hyaluronic acid and platelet-rich plasma, intra-articular
infiltration in the treatment of gonarthrosis. Am J Sports
Med 2012;40:2822-2827.
28. Filardo G, Kon E, Di Martino A, et al. Platelet-rich
plasma vs hyaluronic acid to treat knee degenerative
pathology: study design and preliminary results of a
randomized controlled trial. BMC Musculoskel Disord
2012;13:229.
29. PatelS,DhillonM,AggarwalS,MarwahaN,JainA.
Treatment with platelet-rich plasma is more effective
than placebo for knee osteoarthritis: a prospective,
double-blind, randomized trial. Am J Sports Med 2013;41:
356-364.
30. Sanchez M, Fiz N, Azofra J, et al. A randomized clinical
trial evaluating plasma rich in growth factors (PRGF-
Endoret) versus hyaluronic acid in the short-term treat-
ment of symptomatic knee osteoarthritis. J Arthroscopy
Related Surg 2012;28:1070-1078.
31. Vaquerizo V, Plasencia MA, Arribas I, et al. Comparison of
intra-articular injections of plasma rich in growth factors
(PRGF-Endoret) versus durolane hyaluronic acid in the
treatment of patients with symptomatic osteoarthritis: a
randomized controlled trial. J Arthroscopy Related Surg
2013;29:1635-1643.
32. Raeissadat SA, Rayegani SM, Hassanabadi H, et al. Knee
osteoarthritis injection choices: platelet-rich plasma (PRP)
versus hyaluronic acid (a one-year randomized clinical
trial). Clin Med Insights: Arthritis Musculoskel Disord 2015;8:
1-8.
33. Gobbi A, Karnatzikos G, Mahajan V, Malchira S. Platelet-
rich plasma treatment in symptomatic patients with knee
osteoarthritis: preliminary results in a group of active
patients. Sports Health 2012;4:162-172.
34. Martin P, D’Souza D, Martin J, et al. Wound healing in
the PU.1 null mouse: tissue repair is not dependent on
inflammatory cells. Curr Biol 2003;13:1122-1128.
35. Dragoo JL, Braun HJ, Durham JL, et al. Comparison of the
acute inflammatory response of two commercial platelet-
rich plasma systems in healthy rabbit tendons. Am J Sports
Med 2012;40:1274-1281.
36. Braun HJ, Kim HJ, Chu CR, Dragoo JL. The effect of
platelet-rich plasma formulations and blood products
on human synoviocytes: implications for intra-articular
injury and therapy. Am J Sports Med 2014;42:
1204-1210.
37. Riboh JC, Saltzman BM, Yanke AB, Fortier L, Cole BJ.
Effect of leukocyte concentration on the efficacy of
platelet rich plasma on the treatment of knee osteoar-
thritis. Am J Sports Med. April 29, 2015; [E-pub ahead of
print].
PRP INJECTIONS IN KNEE OSTEOARTHRITIS 11
